a note of caution on the knockout mouse project

CORRESPONDENCE 1132 VOLUME 36 | NUMBER 11 | NOVEMBER 2004 NATURE GENETICS A note of caution on the Knockout Mouse Project To the editor: I read with interest the position papers advocating the generation of mice with mutations in all known genes 1,2 . As a researcher who has long been active in this area, I would like to voice some caution on financial, logistical and scientific grounds. Financially, at a time of tightening budgets, this approach could be sustained only by chipping away at the dwindling pool of investigator-initiated grants to feed a ‘military-industrial’ behemoth of sorts that will attend to the task. Logistically, I take mild issue with the notion that this resource would be either widely useful or readily available. Many of the 415 targeted mutant strains deposited at the Jackson Laboratory have been frozen for lack of takers. If this is any indication of what’s to come, I am not sure that the demand will justify the effort. Scientifically, I challenge the notion that we need to standardize methods to generate null alleles. I can think of many instances in which different null alleles of the same gene generated in different laboratories have resulted in different phenotypes and thus taught us important lessons about gene function. I also argue that shotgun phenotyping for a limited set of parameters, as proposed by the two groups, is unlikely to yield much useful information. Most of the common tests likely to be used measure traits under polygenic, genetically heterogeneous control, and thus, only large effects are likely to be detected. Although I support the creation of a mechanism to facilitate the generation of knockout mice, I suggest that we use some caution before embarking on an endeavor as sweeping as that advocated by my colleagues. Domenico Accili Columbia University College of Physicians & Surgeons, Naomi Berrie Diabetes Center, Department of Medicine, 1150 St. Nicholas Avenue, New York, New York 10032, USA. Correspondence should be addressed to D.A. e-mail: [email protected] 1. The Comprehensive Knockout Mouse Project Consortium. Nat. Genet. 36, 921–924 (2004). 2. The European Mouse Mutagenesis Consortium. Nat. Genet. 36, 925–927 (2004). © 2004 Nature Publishing Group http://www.nature.com/naturegenetics

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Page 1: A note of caution on the Knockout Mouse Project

C O R R E S P O N D E N C E

1132 VOLUME 36 | NUMBER 11 | NOVEMBER 2004 NATURE GENETICS

A note of caution on the Knockout Mouse Project

To the editor:I read with interest the position papersadvocating the generation of mice withmutations in all known genes1,2. As aresearcher who has long been active in thisarea, I would like to voice some caution onfinancial, logistical and scientific grounds.Financially, at a time of tightening budgets,this approach could be sustained only bychipping away at the dwindling pool ofinvestigator-initiated grants to feed a‘military-industrial’ behemoth of sorts thatwill attend to the task. Logistically, I takemild issue with the notion that this resourcewould be either widely useful or readilyavailable. Many of the 415 targeted mutantstrains deposited at the Jackson Laboratory

have been frozen for lack of takers. If this isany indication of what’s to come, I am notsure that the demand will justify the effort.Scientifically, I challenge the notion that weneed to standardize methods to generatenull alleles. I can think of many instances inwhich different null alleles of the same genegenerated in different laboratories haveresulted in different phenotypes and thustaught us important lessons about genefunction. I also argue that shotgunphenotyping for a limited set of parameters,as proposed by the two groups, is unlikely toyield much useful information. Most of thecommon tests likely to be used measuretraits under polygenic, geneticallyheterogeneous control, and thus, only large

effects are likely to be detected. Although Isupport the creation of a mechanism tofacilitate the generation of knockout mice, Isuggest that we use some caution beforeembarking on an endeavor as sweeping asthat advocated by my colleagues.

Domenico Accili

Columbia University College of Physicians &Surgeons, Naomi Berrie Diabetes Center,Department of Medicine, 1150 St. NicholasAvenue, New York, New York 10032, USA.Correspondence should be addressed to D.A.e-mail: [email protected]

1. The Comprehensive Knockout Mouse ProjectConsortium. Nat. Genet. 36, 921–924 (2004).

2. The European Mouse Mutagenesis Consortium. Nat.Genet. 36, 925–927 (2004).

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